The diverse cell types present in the adult organism are produced during development by lineage-specific transcription factors that define and reinforce cell type specific gene expression patterns. Cellular phenotypes are further stabilized by epigenetic modifications that allow faithful transmission of cell-type specific gene expression patterns over the lifetime of an organism (Jenuwein, T. & Allis, C. D. (2001) Science 293, 1074-80; Bernstein, B. E., et al. (2007) Cell 128, 669-81). Recent work by Yamanaka and colleagues showing that four transcription factors are sufficient to induce pluripotency in primary fibroblasts demonstrated that fully differentiated cells can be induced to undergo dramatic cell fate changes (Takahashi, K. & Yamanaka, S. (206) Cell 126, 663-76). Similarly, the transfer of somatic cell nuclei into oocytes, as well as cell fusion of pluripotent cells with differentiated cells have proven to be capable of inducing pluripotency (Briggs, R. & King, T. J. (1952) Proc Natl Acad Sci USA 38, 455-63; Gurdon, J. B., et al. (1958) Nature 182, 64-5; Campbell, K. H., et al. (1996) Nature 380, 64-6; Tada, M., et al. (2001) Curr Biol 11, 1553-8; Do, J. T. & Scholer, H. R. (2004) Stem Cells 22, 941-9; Cowan, C. A., et al. (2005) Science 309, 1369-73). This transformation has been interpreted as a reversion of mature into more primitive developmental states, with a concomitant erasure of developmentally relevant epigenetic information (Silva, J. & Smith, A. (2008) Cell 132, 532-6). The resultant cells may then be reprogrammed to a new cell fate.
Reprogramming into an embryonic state with subsequent differentiation of the embryonic-state cells into cells of the Central Nervous System (CNS) is slow and inefficient, requiring significant time and manipulation in vitro. More useful would be direct reprogramming between divergent somatic lineages. It has been observed that cell fusion or forced expression of lineage-specific genes in somatic cells can induce traits of other cell types (Blau, H. M. (1989) Trends Genet 5, 268-72; Zhou, Q. & Melton, D. A. (2008) Cell Stem Cell 3, 382-8). For example, the basic helix-loop-helix (bHLH) transcription factor MyoD can induce muscle-specific properties in fibroblasts but not hepatocytes (Davis, R. L., et al. (1987) Cell 51, 987-1000; Schafer, B. W., et al. (1990) Nature 344, 454-8); ectopic expression of IL2 and GM-CSF receptors can lead to myeloid conversion in committed lymphoid progenitor cells (Kondo, M. et al. (2000) Nature 407, 383-6); expression of CEBPα in B-cells or Pu.1 and CEBPα in fibroblasts induces characteristics of macrophages (Bussmann, L. H. et al. (2009) Cell Stem Cell 5, 554-66; Feng, R. et al. (2008) Proc Natl Acad Sci USA 105, 6057-62; Xie, H., et al. (2004) Cell 117, 663-76) deletion of Pax5 can induce B-cells to de-differentiate toward a common lymphoid progenitor (Cobaleda, C., et al. (2007) Nature 449, 473-7); and the (bHLH) transcription factor neurogenin3, in combination with Pdx1 and MafA, can efficiently convert pancreatic exocrine cells into functional β-cells in vivo (Zhou, Q., et al. (2008) Nature 455, 627-32).
Publications relevant to conversion of pluripotent cells to neurons include, inter alia, Wu, H. et al. Proc Natl Acad Sci USA 104, 13821-13826 (2007); Johnson et al. J Neurosci 27, 3069-3077 (2007); Zhang et al. Nat Biotechnol 19, 1129-1133 (2001); Elkabetz, et al., Genes Dev 22, 152-165 (2008); Koch et al. Proc Natl Acad Sci USA 106, 3225-3230 (2009); Chambers et al. Nat Biotechnol 27, 275-280 (2009).